CD97 is a member of the adhesion family of G-protein coupled receptors (GPCR) and is normally expressed at high levels constitutively on myeloid cells. In some epithelial cancers CD97 levels have been positively correlated with dedifferentiation and malignant grade. . The primary structure of CD97 suggests a G-protein coupled receptor (GPCR), which utilizes an adhesion class of ligand. We have determined that integrin alpha 5, beta 1 is one binding protein for CD97, and conversely CD97 can act as a ligand to stimulate endothelial cell activation via integrin receptor binding. We recently have discovered that ectopic CD97 leads to specific heterotrimeric G protein activation. Having identified a signaling pathway activated by CD97, it has been possible to assay CD97-binding proteins for signal transducing functions. We have demonstrated that intercellular integrin alpha 5 beta 1 presentation to CD97-expressing cells activates a specific class of heterotrimeric G protein. However, presentation of CD55, another CD97-binding protein, is neither sufficient nor required for such activation. This is the first data that addresses ligand-dependent signal transduction for CD97. In order to address the function of CD97 relative to cancer biology, we have used several approaches that assess invasiveness and tumorigenicity. CD97 is expressed in thyroid, colon, and prostate cancers but not in the normal epithelial counterparts. Reducing CD97 expression in prostate cancer cell lines inhibits their migration and invasion in vitro. CD97-dependent migration has been analyzed in prostate cancer cells with respect to chemoattractant ligands and downstream signaling pathways. These early data suggest that CD97-dependent migration results from the interaction of CD97 with other chemoattractant receptors. Although CD97 is absent in normal thyroid epithelial cells, it has been demonstrated that CD97 expression increases during thyroid cancer dedifferentiation and progression to anaplasia. However, there is no previous evidence of a direct function of CD97 in cancer progression. To address the question of a potential role of CD97 in thyroid cancer development and progression, we generated a CD97 transgenic mouse model constitutively expressing human CD97 in the follicular epithelial cells of the thyroid and crossed this CD97 transgenic mouse with the TRbetaPV/PV mouse. The TRbetaPV/PV mouse spontaneously develops follicular thyroid adenoma with pathological progression to carcinoma, which has similarities to human cancer. Studies have indicated that the TRbetaPV/PV mouse is a valid preclinical mouse model to identify potential molecular targets for the treatment of thyroid cancer. We showed that constitutive expression of CD97 in the follicular epithelium can promote thyroid cancer progression. TRbetaPV/PV mice expressing CD97 exhibited increased occurrence of vascular invasion, a correlate of progression to carcinoma, and lung metastasis with a more aggressive histology than the TRbetaPV/PV mice without CD97. Furthermore, we showed that the expression of CD97 in TRbetaPV/PV mice increased ERK phosphorylation suggesting that CD97 may drive cancer progression by activating this pathway to increase tumor cell migration and invasion. In addition, constitutive CD97 expression resulted in higher Ki67 indicating that CD97 also plays a role in increasing proliferation. The present study provides in vivo evidence for a direct role of CD97 in thyroid cancer progression, suggesting that this G-protein coupled receptor may be an important target for chemotherapeutic intervention of thyroid cancer.